P-glycoprotein Inhibition as Adjunct Treatment for Medically Refractory Epilepsy.

NCT00524134 | Terminated Phase 2 Results DMC

• 1 other identifier: AAAC3821
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

In up to 1 out of 3 patients with epilepsy, seizures continue to occur despite the use of one or more antiepileptic medications. Patients also have significant problems with side-effects of these medications as doses are increased. Our body naturally generates miniature pumps located on the surfaces of many organs to get rid of toxic substances, and antiepileptic medications can be considered by the cells of the body to be a toxin. Research with epileptic brain regions have shown an increase in the amount of drug pumps, therefore getting rid of antiepileptic drugs. One of these pumps is called p-glycoprotein (P-gp for short). Medications may be unable to penetrate and stay within the parts of the brain that need them them most. This may mean that the amount of drug is actually lower in the parts of the brain that cause seizures, and higher in the rest of the brain, which may be why patients may still feel side-effects when seizures are still occurring. Research in animals has shown that blocking the P-gp pumps can improve how bad, and how many seizures occur as well as the length of seizures. Blockage of the pumps can be done using a different type of medication. Some medications that are used for common problems have been discovered to also block P-gp pumps. One of these, carvedilol, is used to treat heart failure and high blood pressure. It has been found to be very safe in these patients, and does not have a lot of side-effects. We plan to add this medication in addition to patient's anti-seizure medications to see if it will improve epileptic seizures. The reason why some patients have high amounts of P-gp pumps and others do not may be related to their genetics. A simple blood test can be used to determine a person's potential to produce high quantities of the pumps. This study will also attempt to show that the genetics will affect how well the P-gp blocking will work.

Conditions

Epilepsy

Keywords

Epilepsy; Seizure; p-glycoprotein

Outcome Measures

Primary Outcomes (1)

• Proportion of Each Treatment Arm With ≥50% Reduction in Seizures

  12 weeks at highest tolerated dose

Secondary Outcomes (3)

• Percent Change in Total Seizure Count Between Treatment Arms

  12 weeks at highest tolerated dose

• Prevalence of Seizure Freedom

  12 weeks at highest tolerated dose

• Prevalence of Medication Retention/Treatment Failure

  16 weeks

Study Arms (1)

1

EXPERIMENTAL

Carvedilol-CR up to 80mg daily, used as a P-glycoprotein inhibitor to increase drug concentrations in specific regions of the brain.

Drug: Carvedilol-CR

Interventions

Carvedilol-CR DRUG

Week 1: 20mg capsule once daily Week 2-3: 40mg capsule once daily Week 4-15: 80mg once daily Week 16: tapering (40mg/day x 4d, then 20mg/day x 3d), unless the patient wishes to continue receiving the medication.

Also known as: Coreg-CR

1

Eligibility Criteria

• Age: 10 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• probable or definite localization-related, primary generalized or symptomatic generalized epilepsy that is medically-refractory, as defined by treatment failure of at least 2 anti-epilepsy drugs at standard doses, despite medication compliance as determined by the treating neurologist
• at least 3 seizures/month in the 3-month period prior to randomization. Seizures that will be considered include generalized tonic clonic, complex partial, myoclonic and absence seizures. Simple partial seizures must have an observable motor component or have been otherwise been documented by videoEEG to be a definite seizure.
• Patients with prior epilepsy brain surgery or vagal nerve stimulator implantation will be allowed if medication and seizure frequency has been stable for the prior 3 months.
• Pre-menopausal women must be utilizing two reliable forms of birth control or abstinence
• ability of the patient to understand the concept of a clinical trial by answering the following questions appropriately: o will your seizures get better, worse or stay the same? Response in the spirit of: Any of the 3 could happen.

You may not qualify if:

• pregnancy or breast-feeding
• systolic blood pressure \<100mmHg
• resting heart rate \< 55 bpm
• concurrent calcium channel, beta-blocker or digoxin therapy
• Known hypersensitivity to carvedilol or any component of the formulation
• Decompensated cardiac failure requiring intravenous inotropic therapy
• Coronary artery disease with history of angina or Any cause of unstable angina
• Second- or third-degree AV block or sick sinus syndrome
• Bronchial asthma or related bronchospastic conditions
• Severe hepatic or renal impairment
• Active drug or alcohol dependence, that, in the opinion of a study investigator, would interfere with adherence to study requirements
• Any acute medical or psychiatric illness requiring inpatient admission; exceptions are elective epilepsy monitoring or elective procedures

Sponsors & Collaborators

• Columbia University: lead
• American Epilepsy Society: collaborator
• Milken Institute: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

Columbia Comprehensive Epilepsy Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Epilepsy; Seizures

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: CU PRS Administrator
• Organization: Columbia University

crchelp@columbia.edu

212-342-1643

Study Officials

• Derek Chong, MD, MSc

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2007
• First Posted: September 3, 2007
• Study Start: December 1, 2008
• Primary Completion: October 1, 2010
• Study Completion: October 1, 2010
• Last Updated: May 23, 2016
• Results First Posted: April 22, 2016

Record last verified: 2016-04

Locations

US (1)